Neural Probes of Respiratory Control and Interoception in Panic Disorder," an application for an NIMH Patient Oriented Research Career Development Award (K23). The candidate has completed neuroimaging fellowship training and seeks advanced training to facilitate objectives for future independent neuroimaging research programs in the mood and anxiety disorders. A neuroimaging study of respiratory interoception in panic disorder will serve as the proposed project. Panic disorder is a serious psychiatric illness that imposes significant social-economic burden given its prevalence of 2-4% in the general population, and high rates (>50%) of treatment non-response and relapse. The pathophysiological basis of panic disorder is unknown, although prevailing models reflect roles for cortico-limbic brain dysfunction and abnormal respiration. The candidate proposes to test a new cortico-limbic/paralimbic model focused on the insularcortex and its role in interoception (the sense of the physiological condition of the body). Intact interoception is essential to survival as an alarm for homeostatic imbalance, and thought to be primarily processed within the insular cortex. While the insular cortex has been implicated in previous panic neuroimaging studies, a unified model for panic neural circuitry with an insular focus has yet to be tested and explained. The proposed neural circuit model attributes dysfunction within insular cortex to trigger the misinterpretation of physical symptoms (interoceptive cues), that in turn lead to exaggerated behavioral/fear responses along a final common panic circuitry. Functional magnetic resonance imaging (fMRI) studies during respiratory interoceptive provocation will be used to test the candidate's neural circuit model for panic disorder, centered on the insular cortex and its role in interoception. Additional tests of acid/base physiology and respiration psychophysiology will complement the neuroimaging studies in order to differentiate a respiratory subtype of panic disorder, reported to account for greater than 50% of panic patients. Taken together, the project represents the first integrated neural systems study of panic disorder with respiratory provocation and control. The project will test a unified model for panic neural circuitry while promising to inform general models of anxiety circuitry. PUBLIC HEALTH RELEVANCE RELEVANCE: The cause of panic disorder (a condition characterized by frequent, spontaneous panic attacks) is unknown and current treatments fail to keep most patients in remission. The current project aims to delineate the dysfunctional brain circuits involved in panic disorder so that better treatments may be developed.